Lawrence Shoemaker

Update of PAX2 mutations in renal coloboma syndrome and establishment of a locus-specific database

Renal coloboma syndrome, also known as papillorenal syndrome is an autosomal‐dominant disorder characterized by ocular and renal malformations. Mutations in the paired‐box gene, PAX2, have been identified in approximately half of individuals with classic findings of renal hypoplasia/dysplasia and abnormalities of the optic nerve. Prior to 2011, there was no actively maintained locus‐specific database (LSDB) cataloguing the extent of genetic variation in the PAX2 gene and phenotypic variation in individuals with renal coloboma syndrome. Review of published cases and the collective diagnostic experience of three laboratories in the United States, France, and New Zealand identified 55 unique mutations in 173 individuals from 86 families. The three clinical laboratories participating in this collaboration contributed 28 novel variations in 68 individuals in 33 families, which represent a 50% increase in the number of variations, patients, and families published in the medical literature. An LSDB was created using the Leiden Open Variation Database platform: www.lovd.nl/PAX2. The most common findings reported in this series were abnormal renal structure or function (92% of individuals), ophthalmological abnormalities (77% of individuals), and hearing loss (7% of individuals). Additional clinical findings and genetic counseling implications are discussed. Hum Mutat 33:457–466, 2012.

Alemtuzumab (Campath-1H) Induction in a Pediatric Heart Transplant: Successful Outcome and Rationale for Its Use

Despite increasing clinical experience in adult transplantation, induction therapy with alemtuzumab (Campath-1H) has rarely been reported in pediatric solid-organ transplants, and has been limited to kidneys, intestine and multi-visceral organs. Basic science research and clinical observations reported from the adult experience suggest potential benefits of alemtuzumab in pediatric organ recipients. We report successful induction therapy with alemtuzumab and steroid-free maintenance therapy for cardiac transplantation in a teenager, and discuss its merits in this patient.

Reduced elastogenesis: a clue to the arteriosclerosis and emphysematous changes in Schimke immuno-osseous dysplasia?

BackgroundArteriosclerosis and emphysema develop in individuals with Schimke immuno-osseous dysplasia (SIOD), a multisystem disorder caused by biallelic mutations in SMARCAL1 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1). However, the mechanism by which the vascular and pulmonary disease arises in SIOD remains unknown.MethodsWe reviewed the records of 65 patients with SMARCAL1 mutations. Molecular and immunohistochemical analyses were conducted on autopsy tissue from 4 SIOD patients.ResultsThirty-two of 63 patients had signs of arteriosclerosis and 3 of 51 had signs of emphysema. The arteriosclerosis was characterized by intimal and medial hyperplasia, smooth muscle cell hyperplasia and fragmented and disorganized elastin fibers, and the pulmonary disease was characterized by panlobular enlargement of air spaces. Consistent with a cell autonomous disorder, SMARCAL1 was expressed in arterial and lung tissue, and both the aorta and lung of SIOD patients had reduced expression of elastin and alterations in the expression of regulators of elastin gene expression.ConclusionsThis first comprehensive study of the vascular and pulmonary complications of SIOD shows that these commonly cause morbidity and mortality and might arise from impaired elastogenesis. Additionally, the effect of SMARCAL1 deficiency on elastin expression provides a model for understanding other features of SIOD.

Midaortic Syndrome Presenting as Neonatal Hypertension

We describe a case of mid-aortic syndrome presenting as systemic hypertension in infancy and early childhood. Angiography of the descending and abdominal aorta is the diagnostic test of choice to confirm the diagnosis of mid-aortic syndrome. Severity of hypertension is one of the major factors in determining the timing of intervention. Because of variability in the anatomic extent of mid-aortic syndrome, management options need to be individualized.

Schimke immunoosseous dysplasia: defining skeletal features

Schimke immunoosseous dysplasia (SIOD) is an autosomal recessive multisystem disorder characterized by prominent spondyloepiphyseal dysplasia, T cell deficiency, and focal segmental glomerulosclerosis. Biallelic mutations in swi/snf-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1 (SMARCAL1) are the only identified cause of SIOD, but approximately half of patients referred for molecular studies do not have detectable mutations in SMARCAL1. We hypothesized that skeletal features distinguish between those with or without SMARCAL1 mutations. Therefore, we analyzed the skeletal radiographs of 22 patients with and 11 without detectable SMARCAL1 mutations. We found that patients with SMARCAL1 mutations have a spondyloepiphyseal dysplasia (SED) essentially limited to the spine, pelvis, capital femoral epiphyses, and possibly the sella turcica, whereas the hands and other long bones are basically normal. Additionally, we found that several of the adolescent and young adult patients developed osteoporosis and coxarthrosis. Of the 11 patients without detectable SMARCAL1 mutations, seven had a SED indistinguishable from patients with SMARCAL1 mutations. We conclude therefore that SED is a feature of patients with SMARCAL1 mutations and that skeletal features do not distinguish who of those with SED have SMARCAL1 mutations.

Severe calcification of the aorta (porcelain aorta) associated with sarcoidosis in a pediatric heart transplant recipient.

Das BB, Shoemaker L, Kim E, Mascio CE, Austin EH. Severe calcification of the aorta (porcelain aorta) associated with sarcoidosis in a pediatric heart transplant recipient.

Conjunctive effects of fibroblast growth factor and glycosaminoglycan on bone metabolism in neonatal bartter syndrome.

The calciotropic activity of urine from a subject with neonatal Bartter syndrome (NBS) has been partially purified using ion-exchange and gel chromatographic techniques. A bioassay using bone disk from rat calvaria was used to estimate calciotropic activity, which in the urine of the subject with NBS appears to be due to basic fibroblast growth factor (bFGF) bound to a glycosaminoglycan susceptible to heparitinase digestion. The calciotropic activity is eluted from DEAE-Sephacel and Sepharose CL-6B in a narrow band in association with metachromatic material and is destroyed by heparitinase and blocked by an antibody to bFGF. After treatment of purified preparations with heparitinase, a component that is inactive alone but develops calciotropic activity in association with heparin can be isolated by affinity chromatography on heparin-Sepharose columns. This component is recovered from the column at NaCl concentrations expected to elute bFGF and is inactivated by antibodies to bFGF. No calciotropic activity can be shown in glycosaminoglycan-containing fractions from urine from a normal boy or a normal man, but such fractions exhibit calciotropic activity if bFGF is added to the assay system. When bFGF is added to urine from either normal subject followed by ion-exchange chromatography on DEAE-Sephacel, calciotropic activity is eluted at NaCl concentrations closely similar to those found to elute calciotropic activity from the urine of the NBS subject. It appears that the abnormal findings in NBS urine are due to excess bFGF, although they could be due to some abnormality of the glycosaminoglycan component.

Neonatal Bone Mineral Uptake Is Measurably Affected by Local pH and Concentrations of Inorganic Phosphate, Ionized Calcium and Ionized Magnesium

Neonatal Bone Mineral Uptake Is Measurably Affected by Local pH and Concentrations of Inorganic Phosphate, Ionized Calcium and Ionized Magnesium

Contrasting Phenotypes of Children with Different Bartter's Syndrome (BS) Gene Defects |[dagger]| 483

BS describes a phenotype of renal sodium wasting, hypokalemic metabolic alkalosis, elevated plasma renin and aldosterone with normal blood pressure, and normal serum magnesium. To date, mutations in 3 genes encoding thick ascending limb transporters have been identified in BS; NKCC2, ROMK, and CLCNKB. Children with NKCC2 and ROMK defects are premature with polyhydramnios, hypercalciuria and nephrocalcinosis. In contrast, children with CLCNKB defect are premature with polyhydramnios, but do no have nephrocalcinoisis.